Editor's Note: At a recent international academic conference, Professor Matthew Davids from the Dana-Farber Cancer Institute in the United States announced the interim analysis results of the Phase 3 randomized controlled clinical trial, BRUIN CLL-322. This study aimed to evaluate the efficacy and safety of fixed-duration pirtobrutinib plus venetoclax and rituximab (PVR regimen) versus venetoclax plus rituximab (VR regimen) in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).01 Research Background: Addressing Unmet Needs in Covalent BTKi-Experienced Patients
Chronic lymphocytic leukemia (CLL) remains largely incurable. With the widespread use of covalent BTK inhibitors (cBTKi, such as ibrutinib, acalabrutinib, and zanubrutinib) and BCL-2 inhibitors (such as venetoclax), there is an urgent clinical need to explore optimal treatment strategies following the sequential use of these agents. Pirtobrutinib, as the first and currently only approved non-covalent (reversible) BTK inhibitor, demonstrated favorable efficacy in cBTKi-experienced patients in earlier studies. BRUIN CLL-322 is the first Phase 3 trial to evaluate its use in a fixed-duration combination regimen against the standard second-line regimen (VR).
02 Study Design: Fixed-Duration Combination Treatment Strategy
BRUIN CLL-322 (NCT04965493) is a randomized, open-label, global multicenter Phase 3 trial. A total of 639 patients with CLL/SLL who had received at least one prior line of therapy were enrolled, and prior cBTKi use was permitted. Patients were randomized 1:1 to: • PVR Group (n=321): Pirtobrutinib (Cycles 1–28) + Venetoclax (Cycles 3–25) + Rituximab (Cycles 3–8). • VR Group (n=318): Venetoclax (Cycles 1–24) + Rituximab (Cycles 1–6).
The primary endpoint was progression-free survival (PFS) as assessed by an Independent Review Committee (IRC).
03 Core Results: Significant PFS Benefit with a 45% Reduction in Risk
With a median follow-up of 30.6 months, the results showed that PFS in the PVR group was significantly superior to that in the VR group: • Hazard Ratio (HR): 0.547 (95% CI: 0.429–0.697), P < 0.0001. • 24-month PFS Rate: 86.9% for the PVR group and 71.8% for the VR group.
This indicates that the PVR regimen reduced the risk of disease progression or death by 45.3% compared to the VR regimen. Furthermore, investigator-assessed PFS was highly consistent with the IRC results (HR 0.487).
04 Subgroup Analysis: Outstanding Advantages in Covalent BTKi-Resistant Populations
The advantage of the PVR regimen remained robust across the cBTKi-experienced subgroups: • All cBTKi-experienced patients: HR was 0.50. • Patients who discontinued cBTKi due to progressive disease: HR was 0.44. • Patients with only one prior line of cBTKi therapy who progressed (a common high-risk clinical population): HR reached 0.323, with a 24-month PFS rate of 88.4% in the PVR group versus 51.6% in the VR group.
Additionally, consistent clinical benefits for the PVR group were observed across high-risk genetic subgroups, including those with TP53 mutations, deletion 17p, and unmutated IGHV.
05 Deep Response: Significant Improvement in uMRD Rates and Depth of Response
In evaluable samples, the PVR regimen significantly increased the rate of undetectable minimal residual disease (uMRD). At the end of Cycle 25 (end of treatment): • uMRD4 (<10⁻⁴) rate: 86.3% in the PVR group, significantly higher than 60.7% in the VR group. • At deeper MRD levels (10⁻⁵ and 10⁻⁶), the PVR group also demonstrated higher rates of conversion to negativity. • Objective Response Rate (ORR): 88% for the PVR group vs. 83% for the VR group; the complete response (CR/CRi) rates were 32% and 23%, respectively.
06 Safety Evaluation: Well-Tolerated with Controllable Cardiovascular Risk
The safety profile of the PVR regimen was consistent with the known safety characteristics of the individual agents: • Neutropenia: This was the most common Grade 3 or higher adverse event (AE), with an incidence of 50% in the PVR group and 43% in the VR group. • Infection: Grade 3 or higher infection rates were 34% in the PVR group and 23% in the VR group. • Cardiovascular AEs: Notably, the incidence of atrial fibrillation/flutter was 3.1% in the PVR group and 3.2% in the VR group, showing no significant difference. The incidence of hypertension was slightly higher in the PVR group (12% vs. 7%). • Discontinuation Rate: The proportion of patients discontinuing treatment due to treatment-related AEs was low in both groups (approximately 5%).
07 Expert Conclusions and Outlook
Professor Matthew Davids noted that BRUIN CLL-322 is the first study to demonstrate that adding a non-covalent BTKi (pirtobrutinib) to the fixed-duration VR regimen significantly improves outcomes for patients with relapsed/refractory CLL. Particularly in the cBTKi-experienced population, the PFS in the VR group (71.8%) was notably lower than data observed in the previous MURANO study (approx. 85%), reflecting the higher biological risk of contemporary cBTKi-experienced patients. With its superior PFS benefit, higher uMRD rates, and favorable safety profile, the PVR regimen is expected to become a new standard-of-care second-line option for patients with previously treated CLL/SLL, regardless of prior cBTKi exposure.
